The present invention relates to new inhibitors of matrix metalloproteinases (hereinafter MMPs), to a process for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in the prevention, control and treatment of diseases in which the proteolytic action of MMPs is involved.
Certain disease states are characterised by an imbalance of active MMPs and their natural inhibitors, the tissue inhibitors of metalloproteinases (hereinafter TIMPs). When TIMP levels are insufficient, a progressive slow degradation of the extracellular matrix occurs, for example cartilage matrix loss in rheumatoid arthritis (L. A. Walakovits et al., Arthritis Rheum, 35:35-42, 1992) and osteoarthritis (D. D. Dean et al., J. Clin. Invest., 84:678-685, 1989), and bone matrix degradation in osteoporosis (p. A. Hill et al., Biochem. J., 308:167-175, 1995). In other situations, such as congestive heart failure, rapid degradation of the heart""s extracellular matrix occurs (P. W. Armstrong et al., Canadian J. Cardiol. 10:214-220, 1994). Cancer cells use MMPs, either expressed by themselves or by the surrounding tissues, to achieve rapid remodelling of the extracellular matrix. There is considerable evidence that MMPs are involved in at least 3 aspects of the growth and spread of tumors (e.g., see A. H. Davidson et al., Chemistry and Industry, 258-261, 1997, and references therein). In the process of tumor metastasis, MMPs are used to break down the extracellular matrix, allowing primary tumor cancer cells to invade neighbouring blood vessels where they are transported to different organs and establish secondary tumors. The invasive growth at these secondary sites also needs MMPs to help break down tissue. In addition, MMP activity contributes to the invasive in-growth of new blood vessels (angiogenesis) which is required for tumors to grow above a certain size.
Low molecular weight compounds able to inhibit one or more of the matrix metalloproteinases, in particular stromelysin-1 (M-3; EC 3.4.24.17), gelatinase A (MMP-2; EC 3.4.24.24), gelatinase B (MM-9; EC 3.4.24.35), neutrophil collagenase or collagenase-2 (MMP-8; EC 3.4.24.34), interstitial collagenase or collagenase-1 (MMP-1; EC 3.4.27.7), matrilysin (MMP-7; EC 3.4.24.23), collagenase-3 (MMP-13), and the membrane-type metalloproteinase (MT-MMPs: MMP-14, MNP-15, MMP-16, MMP-17) are currently considered as promising therapeutic agents in degenerative, tumoral and autoimmune pathologies (e.g., P. D. Brown: xe2x80x9cMatrix metalloproteinase inhibitors: A new class of anticancer agentxe2x80x9d, Curr. Opin. Invest. Drugs, 2:617-626, 1993; A. Krantz: xe2x80x9cProteinases in Inflammationxe2x80x9d, Annu. Rep. Med. Chem. 28:187-195, 1993). Many of such compounds described hitherto are peptide derivatives or pseudopeptides, bearing analogies to recognized peptide substrates of these enzymes, and characterized in addition by a functional group capable of binding the Zn (II) atom present in the catalytic site of said enzymes. Known classes of MMP inhibitors include those in which the Zn binding group is a hydroxamic acid, and the skeleton, as represented in the general formula (A), mimicks the amino acid sequence of collagen at the site cleaved by collagenase: 
wherein Ra, Rb, Rc, and Rd are hydrogen atoms or appropriate substituents (e.g., N. R. A. Beeley et al., xe2x80x9cInhibitors of matrix metalloproteinases (MMP""s)xe2x80x9d, Curr. Opin. Ther. Patents 4:7-16, 1994; J. R. Porter et al., xe2x80x9cRecent developments in matrix metalloproteinase inhibitorsxe2x80x9d, Exp. Opin. Ther. Patents 5:1287-1296, 1995; J. R. Morphy et al., xe2x80x9cMatrix metalloproteinase inhibitors: Current statusxe2x80x9d, Curr. Med. Chem. 2:743-762, 1995; R. P. Beckett et al., xe2x80x9cRecent advances in matrix metalloproteinase researchxe2x80x9d, DDT 1:16-26, 1996). Said MMP inhibitors of the prior art can be described as xe2x80x9cpeptide-based hydroxamatesxe2x80x9d or xe2x80x9csubstrate-basedxe2x80x9d inhibitors (e.g., A. H. Davidson et al., xe2x80x9cThe inhibition of matrix metalloproteinase enzymesxe2x80x9d, Chemistry and Industry, 258-261, 1997).
Although MMPs have been recognized as drug targets for at least 20 years, and potent MMP inhibitors described by formula (A) have been disclosed since 1986 or before (e.g., see J. P. Dickens et al., U.S. Pat. No. 4,599,361), no drug of this type has arrived at the market yet. This is not because of questions about the therapeutic potential of MMP inhibitors, but because of problems of xe2x80x9cpeptide-based hydroxamatesxe2x80x9d, such as aqueous solubility, metabolic stability, and other desirable properties, oral bioavailability in particular (e.g., J. R. Porter, reference above; J. Hodgson, xe2x80x9cRemodelling MMPIsxe2x80x9d, Biotechnology 13:554-557, 1995). For example, it is well known that most xe2x80x9cpeptide-based hydroxamatesxe2x80x9d of general formula (A) are rapidly glucuronidated, oxidized to the carboxylic acid, and excreted in the bile (e.g., see J. Singh et al., Bioorg. Med. Chem. Lett. 5:337-342, 1995, and other references above). Finally, another type of problem of the known inhibitors described by general formula (A) may be one of tolerability. This problem is emerging for the most advanced MMP inhibitor in the clinic, marimastat (formula A; Ra=OH, Rb=CH2CHMe2, Rc=CMe3, Rd=Me), which was reported to give muscoloskeletal problems in humans. We have extended these observations by developing an animal model of tolerability with MMP inhibitors (S. Castellino et al., unpublished), involving intraperitoneal administration of the latter in rats for 10 consecutive days, and histological evaluation of stifle joints at the end of treatment. In this model, peptide-based MMP inhibitors of the prior art, e.g. Roche Ro31-9790 (formula A; Ra=H, Rb=CH2CHMe2, Rc=CMe3, Rd=Me), at daily doses of 150 mg/kg or less, elicited hypertrophic fibrosis of stifle ligaments, interstitial hypertrophic fibrosis of skeletal muscles, hypertrophic fibroplasia of the periostium and synovium, and chondrosysplasia and decreased endochondrial ossification of the ephyseal plate. Although the precise reasons for these side-effects are not known at present, they support a strong need for better and diversified molecules, especially as far as the properties referred to above are concerned.
The present invention is concerned with novel MMP inhibitors, specifically characterized by the presence of a nitrogen atom as a substituent at the carbon atom next to the zinc-binding group, and with less or no peptidic character, as compared to substrate-based inhibitors of the prior art.
The present invention provides a compound which is an amine derivative of formula (I) 
wherein
W is xe2x80x94CONHOH or xe2x80x94COOH;
R1 and R2, which are the same or different, are each hydrogen or
a group G, which is methyl, C2-C10 alkyl, C2-C10 alkenyl, C3-C7 cycloalkyl, cycloalkyl-C1-C10-alkyl, aryl, aryl-C1-C10-alkyl, aryl-C2-C10-alkenyl, heterocyclyl, heterocyclyl-C1-C10-alkyl or heterocyclyl-C2-C10-alkenyl, the said methyl, alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl groups being unsubstituted or substituted by one to three substituents; or
xe2x80x94SO2xe2x80x94G, wherein G is as defined above; or
xe2x80x94SOxe2x80x94G, wherein G is as defined above; or
xe2x80x94COxe2x80x94G, wherein G is as defined above; or
xe2x80x94COOxe2x80x94G, wherein G is as defined above; or
xe2x80x94SO2xe2x80x94NH2, xe2x80x94SO2xe2x80x94NHG or xe2x80x94SO2xe2x80x94NGGxe2x80x2, wherein G is as defined above and Gxe2x80x2, which is the same or different, is as defined above for G, or G and Gxe2x80x2, together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or
a group xe2x80x94CONH2, xe2x80x94CONHG or xe2x80x94COxe2x80x94NGGxe2x80x2 wherein G and Gxe2x80x2 are as defined above, or G and Gxe2x80x2, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or
R1 and R2, taken together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom;
R3 is C1-C15 alkyl, either unsubstituted or substituted by a C3-C7 cycloalkyl group, the alkyl and/or the cycloalkyl group being either unsubstituted, or substituted by one to three substituents selected from methyl, ethyl, C3-C4 linear or branched alkyl, fluoro, chloro, C1-C4 alkoxy, nitro, amino, dimethylamino, carboxy and carboxymethyl; or
R3 is a group xe2x80x94Rxe2x80x94Xxe2x80x94R1 wherein R is a chemical bond, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)mxe2x80x94 wherein m is an integer from 2 to 5, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, phenylene (i.e., xe2x80x94C6H4xe2x80x94), xe2x80x94CH2CHxe2x95x90CHxe2x80x94C6H4xe2x80x94, xe2x80x94CH2CH2CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CCxe2x80x94, xe2x80x94CH2CH2xe2x80x94CCxe2x80x94, xe2x80x94CH2CH2CHxe2x95x90CHxe2x80x94C6H4xe2x80x94, xe2x80x94CH2xe2x80x94CCxe2x80x94C6H4xe2x80x94, or xe2x80x94CH2CH2xe2x80x94CCxe2x80x94C6H4xe2x80x94; X is a direct bond, an oxygen atom, a sulfur atom, or a sulfinyl xe2x80x94S(O)xe2x80x94, sulfonyl xe2x80x94S(O)2 or carbamoyl group xe2x80x94CONHxe2x80x94 or xe2x80x94NHCOxe2x80x94; and R1 is C1-C6 alkyl, C2-C6 alkenyl, phenyl, phenyl-(C1-C6)-alkyl, phenyl-(C2-C6)-alkenyl, heterocyclyl, or heterocyclyl-(C1-C6)-alkyl, either unsubstituted or substituted by a group selected from F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl;
Q, being a secondary or tertiary carboxyamide, is:
a group xe2x80x94CONHG or xe2x80x94CONGGxe2x80x2, wherein G and Gxe2x80x2 are as defined above; or
a group xe2x80x94CONHxe2x80x94CHGGxe2x80x2, wherein G and Gxe2x80x2 are as defined above; or a group xe2x80x94CONGxe2x80x3xe2x80x94CHGGxe2x80x2, wherein Gxe2x80x3, being the same or different, is defined as G above; or
a group xe2x80x94CONHxe2x80x94CH2xe2x80x94CHGGxe2x80x2 or a group xe2x80x94CONGxe2x80x3xe2x80x94CH2xe2x80x94CHGGxe2x80x2, wherein G, Gxe2x80x2 and Gxe2x80x3 are as defined above; or
a group xe2x80x94CO-azaheterocyclyl, wherein azaheterocyclyl, which is either unsubstituted or substituted, is as defined below; with the proviso that when Q is xe2x80x94CONHG, and G is methyl, alkyl-methyl, cycloalkyl-methyl, aryl-methyl or hetherocyclyl-methyl, then such methyl or substituted methyl cannot be further substituted by a group xe2x80x94(CH2)txe2x80x94CO2H, wherein t is 0, or esters and amides thereof,
and a pharmaceutically acceptable salt, solvate or hydrate thereof.
As used herein the term xe2x80x9calkylxe2x80x9d refers to a straight or branched chain alkyl moiety having from 1 to 10 carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl and so on. The term xe2x80x9calkenylxe2x80x9d as used herein refers to a straight or branched chain alkenyl moiety having from 2 to 10 carbon atoms and having in addition one double bond of either E or Z stereochemistry where applicable. Examples of alkenyl groups are: vinyl, allyl, metallyl, butenyl, crotyl and so on.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a saturated carbocyclic group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
The term xe2x80x9carylxe2x80x9d as used herein refers to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms, such as phenyl, naphthyl, indanyl; furthermore, xe2x80x9carylxe2x80x9d as used herein may refer to a diphenyl group (xe2x80x94C6H4xe2x80x94C6H5), a 4-pyridyl-phenyl group, and a methylenedioxyphenyl group.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein refers to a 3- to 7-membered, saturated or unsaturated heterocyclyl ring, containing at least one heteroatom selected from O, S and N, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; and wherein said heterocyclyl ring may be optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclyl ring, or to a C3-C7 cycloalkyl ring, or to a benzene or naphthalene ring. Examples of heterocyclyl groups are pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl thienyl, tetrahydrothienyl, furyl, tetrahydrofuryl, aziridinyl, oxiranyl, azetidinyl, succinimido, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyridazinyl, hexahydropyridazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, benzothienyl, benzothiazolyl, benzoxazolyl isobenzofuranyl, benzofuranyl, benzimidazolyl, indazolyl, chromenyl, indolyl, oxindolyl, phthalimido, 1-oxo-2-isoindolyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, indolizinyl, isoindolyl, 2-oxoisoindolyl, quinuclidinyl, hydantoinyl, saccarinyl, cinnolinyl, purinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepinyl and so on.
The term xe2x80x9cazaheterocyclylxe2x80x9d as used herein includes any of the heterocyclyl groups, as defined above, containing at least one nitrogen atom, said heterocyclyl group being linked to the rest of the molecule by a nitrogen atom.
Substituents which may be present in the methyl, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl and azaheterocyclyl groups in any of the above specifications include the following ones:
a group xe2x80x94(CH2)txe2x80x94Hal, wherein Hal is halo (i.e., fluoro, bromo, chloro or iodo), and t is an integer from 0 to 3;
a group xe2x80x94(CH2)txe2x80x94CF3, or a group xe2x80x94(CH2)txe2x80x94CHF2, wherein t is as defined above,
a group xe2x80x94CH2)txe2x80x94OH, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94ORII, wherein t is as defined above, and RII is straight or branched C1-C6 alkyl, aryl, arylmethyl, heterocyclyl, or heterocyclylmethyl, optionally substituted by hydroxy, methoxy, methyl amino, methylamino, dimethylamino, chloro and fluoro;
a group xe2x80x94(CH2)txe2x80x94OC(O)RII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94OC(O)ORII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94OC(O)NH2, or xe2x80x94(CH2)txe2x80x94OC(O)NHRII, or xe2x80x94(CH2)txe2x80x94OC(O)NRIIRIII, wherein t is as defined above, RII is as defined above, and RIII, being the same or different, is defined as RII above; or RII and RIII taken together with the nitrogen atom form an azaheterocycl ring;
oxo;
a group xe2x80x94(CH2)txe2x80x94NO2, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94N3, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94CN, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94SH, wherein t is as defined above, and acetyl or phenylacetyl esters thereof (i.e., xe2x80x94(CH2)txe2x80x94SCOCH3 and xe2x80x94(CH2)txe2x80x94SCOCH2C6H5);
a group xe2x80x94(CH2)txe2x80x94NH2, or xe2x80x94(CH2)txe2x80x94NHRII, or xe2x80x94(CH2)txe2x80x94NRIIRIII, wherein t, RII and RIII are as defined above, or RII and RIII taken together with the nitrogen atom form an azaheterocyclyl ring;
a group xe2x80x94(CH2)txe2x80x94NHC(O)RII, or xe2x80x94(CH2)txe2x80x94NRIIC(O)RIII, or xe2x80x94(CH2)txe2x80x94NHC(O)ORII, wherein t, RII and R III are as defined above;
a group xe2x80x94(CH2)txe2x80x94NH(CO)NH2, or xe2x80x94(CH2)txe2x80x94NH(CO)NHRII, or xe2x80x94(CH2)txe2x80x94NH(CO)NRIIRIII, wherein t, RII and RIII are as defined above, including the special case wherein RII and RIII taken together with the nitrogen atom form an azaheterocyclyl ring;
a group xe2x80x94(CH2)txe2x80x94NHSO2RII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94NH(SO2)NH2, or xe2x80x94(CH2)txe2x80x94NH(SO2)NHRII, or xe2x80x94(CH2)txe2x80x94NH(SO2)NRIIRIII, wherein t, RII and RIII are as defined above, including the special case wherein RII and RIII taken together with the nitrogen atom form an azaheterocyclyl ring;
a group xe2x80x94(CH2)txe2x80x94NHC(xe2x95x90NH)NH2, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94CHO, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94C(O)RII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94CO2H, wherein t is as defined above, or esters or amides thereof, i.e., xe2x80x94(CH2)txe2x80x94CO2RII, xe2x80x94(CH2)txe2x80x94CONH2, xe2x80x94(CH2)txe2x80x94CONHRII, xe2x80x94(CH2)txe2x80x94CONRIIRIII, wherein RII and RIII are as defined above, including the special case wherein RII and RIII, taken together with the nitrogen atom form an azaheterocyclyl ring;
a group xe2x80x94(CH2)txe2x80x94SO3H, wherein t is as defined above;
a group xe2x80x94(CH2)txe2x80x94S(O)RII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94SO2RII, wherein t and RII are as defined above;
a group xe2x80x94(CH2)txe2x80x94SO2NH2, or xe2x80x94(CH2)txe2x80x94SO2NHRII, or xe2x80x94(CH2)txe2x80x94SO2NRIIRIII, wherein t, RII and RIII are as defined above;
C1-C6 alkyl or C2-C6 alkenyl;
C3-C7 cycloalkyl;
phenyl, biphenyl (i.e., xe2x80x94C6H4xe2x80x94C6H5), methylenedioxyphenyl, methylenedioxyphenylmethyl (hereinafter piperonyl), benzyl, phenethyl, phenpropyl, naphthyl, naphthylmethyl, naphthylethyl, naphthylpropyl, either unsubstituted or substituted by one to three substituents selected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, chloro and fluoro.
When present carboxy, hydroxy, mercapto and amino groups may be either free or in a protected form. Protected forms of said groups are any of those generally known in the art, as described, for example, by T. W. Greene in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Wiley Interscience. Preferably, carboxy groups are protected as esters thereof, in particular methyl, ethyl, tert-butyl, benzyl, and 4-nitrobenzyl esters. Preferably, hydroxy groups are protected as ethers or esters thereof, in particular methoxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, acetates, benzoates, pivalates. Preferably, mercapto groups are protected as thioethers or thioesters, in particular tert-butyl thioethers, thioacetates, thiobenzoates. Preferably, amino groups are protected as carbamates, e.g. tert-butoxycarbonyl and benzyloxycarbonyl derivatives, or as amides, e.g. acetamides and benzamides.
The present invention provides the salts of those compounds of formula (I) that have salt-forming groups, especially the salts of the compounds having an acid group, especially a carboxylic group, a N-hydroxycarbamoyl group, and a sulfo group, or the salts of the compounds having a basic group, especially an amino or guanidino group. The salts are especially physiologically tolerable salts, for example alkali metal and alkaline earth metal salts (e.g. sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with an appropriate organic amine or amino acid (e.g. arginine, procaine salts), and the addition salts formed with suitable inorganic acids (e.g. hydrochlorides, hydrobromides, sulfates, phosphates) or carboxylic and sulfonic organic acids (e.g. acetates, trifluoroacetates, citrates, succinates, malonates, lactates, tartrates, fumarates, maleates, methanesulfonates, p-toluenesulfonates). Some compounds of formula (I) which contain a carboxylate and an ammonium group may exist as zwitterions; such salts are also part of the present invention.
Furthermore, hydrates, solvates of compounds of formula (I), and physiologically hydrolyzable derivatives (i.e., prodrugs) of compounds of formula (I) are included within the scope of the present invention. Particularly preferred prodrugs of the compounds of formula (I) are ester derivatives. They include esters of compounds of formula (I) wherein W is xe2x80x94COOH, or wherein a carboxy group is present in any of the substituents R1, R2, R3 and Q, which may be obtained by condensation of such carboxy group with a pharmaceutically acceptable alcohol, e.g. ethanol, or esters of compounds of formula (I) wherein a hydroxy group is present in any of the substituents R1, R2, R3 and Q, which may be obtained by condensation of such hydroxy group with a pharmaceutically acceptable carboxylic acid, e.g. acetic acid, pivalic acid, benzoic acid and the like. Other particularly preferred prodrugs within the present invention are the cyclic condensation products between compounds of formula (I), wherein W is xe2x80x94CONHOH and R1 is hydrogen, and formaldehyde, or an aldehyde of formula Txe2x80x94CHO, or a ketone of formula TTxe2x80x2CO, wherein T and Txe2x80x2 are carbon radicals, such as tower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, chloro and fluoro. Such condensation products, which are represented herebelow, are obtained by mixing the two components, optionally in the presence of acid catalysts, as those employed for the formation of ketals from alcohols and ketones, and removing water by evaporation, azeotropically or by molecular sieves. 
The present invention encompasses all the possible stereoisomers (e.g. diastereoisomers, epimers, geometrical isomers) of the compounds of formula (I), as well as their racemic or optically active mixtures.
The present invention also includes, within its scope, pharmaceutical compositions comprising one or more of the compounds (I) as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if desirable.
Preferred compounds within the present invention have the structure (Ixe2x80x2): 
wherein:
W is xe2x80x94CONHOH or xe2x80x94COOH;
R1 and R2 are:
both hydrogen; or
both C1-C4 alkyl, still preferably methyl; or
R1 is hydrogen or methyl, and R2 is a group G which is:
C1-C10 alkyl or C2-C10 alkenyl, either unsubstituted or substituted by C3-C7 cycloalkyl, or by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, amino, methylamino, dimethylamino, xe2x80x94CONH2, xe2x80x94CONHCH3 or xe2x80x94CONHC(CH3)3, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl group may in turn be substituted by chloro, fluoro, methoxy or methyl; or
C3-C7 cycloalkyl; or
an aryl group, more preferably phenyl, methylenedioxyphenyl naphthyl or indanyl, each of which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, phenyl, benzyl, phenethyl, phenpropyl, naphthyl and pyridyl, and wherein any phenyl, naphthyl and pyridyl ring may in turn be substituted by one to three substituents selected from chloro, fluoro, methyl, hydroxy, methoxy, amino, methylamino and dimethylamino, or
an unsaturated heterocyclyl group selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, benzimidazolyl, indazolyl, chromenyl, indolyl, oxindolyl, quinolyl, isoquinolyl, isoindolyl, cinnolinyl and purinyl, each of which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or
a saturated or partially saturated heterocyclyl group selected from pyrrolidinyl, tetrahydrothienyl, tetrahydrofuryl, aziridinyl, oxiranyl, azetidinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, tetrahydropyranyl, 1-oxo-2-isoindolyl, tetrahydroisoquinolyl, hydantoinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepinyl and thiazolidinyl, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; and the derivates thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or
C1-C10 alkyl, substituted by any of the unsaturated or saturated heterocyclyl groups as defined above, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; or a derivative thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, xe2x80x94CONH2, xe2x80x94CONHCH3 and xe2x80x94CONHC(CH3)3, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or
C1-C10 alkyl, substituted by any of the aryl group as defined above, and the derivates thereof substituted by one to three substituents selected from chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl ring may be substitued by chloro, fluoro, methoxy or methyl; or
R1 is hydrogen or methyl, and R2 is xe2x80x94SO2xe2x80x94G, wherein G is as defined above; or
R1 is hydrogen or methyl, and R2 is xe2x80x94COxe2x80x94G, wherein G is as defined above; or
R1 is hydrogen or methyl, and R2 is xe2x80x94COxe2x80x94Oxe2x80x94G, wherein G is as defined above; or
R1 is hydrogen or methyl, and R2 is xe2x80x94SO2xe2x80x94NH2, xe2x80x94SO2xe2x80x94NHG or xe2x80x94SO2xe2x80x94NGGxe2x80x2, wherein G is as defined above and Gxe2x80x2, which is the same or different, is as defined above for G; or
R1 is hydrogen or methyl, and R2 is xe2x80x94SOxe2x80x94NHxe2x80x94G, wherein 6 is as defined above; or
R1 is hydrogen or methyl, and R2 is xe2x80x94CONHG or xe2x80x94CONGGxe2x80x2, wherein G is as defined above and Gxe2x80x2, which is the same or different, is as defined above for G; or
R1 and R2, taken together with the nitrogen atom to which they are attached, form a 3- to 7-membered azaheterocyclyl ring, optionally containing N, O, S or SO2 as an additional ring member, which may be substituted by oxo on one or two carbon ring atoms adjacent to the linking nitrogen atom, and which is optionally fused with a benzene ring, the azaheterocyclyl group being either unsubstituted or substituted at one or more carbon and/or nitrogen atoms by chloro, fluoro, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, phenyl, 4-fluorophenyl, benzyl, 4-fluorobenzyl, alpha-methylbenzyl, methylenedioxyphenyl, 2-phenethyl, 2-(4-fluorophenyl)ethyl, piperonyl, carbamoyl, xe2x80x94CONHCH3, xe2x80x94CONHC(CH3)3, xe2x80x94CONH-(4-fluorophenyl), xe2x80x94CONH-pyridyl, xe2x80x94CONH-(methylenedioxy)phenyl xe2x80x94CONH-piperonyl; or
R1 is hydrogen or methyl and R2 is xe2x80x94SO2-azaheterocyclyl, wherein azaheterocyclyl is as defined above; or
R1 is hydrogen or methyl, and R2 is xe2x80x94CO-azaheterocyclyl, wherein azaheterocyclyl is as defined above;
R3 is xe2x80x94CH2-alkyl, xe2x80x94(CH2)n-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-alkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)m-aryl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)m-heterocyclyl, xe2x80x94(CH2)nxe2x80x94S-alkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)m-aryl, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)m-heterocyclyl, xe2x80x94(CH2)nxe2x80x94SO-alkyl, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)m-aryl, xe2x80x94(CH2)nxe2x80x94SOxe2x80x94(CH2)m-heterocyclyl, xe2x80x94(CH2)nxe2x80x94SO2-alkyl, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)m-aryl, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94(CH2)m-heterocyclyl, xe2x80x94(CH2)nxe2x80x94COxe2x80x94alkyl, xe2x80x94(CH2)nxe2x80x94COxe2x80x94(CH2)m-cycloalkyl, xe2x80x94(CH2)nxe2x80x94COxe2x80x94(CH2)m-aryl or xe2x80x94(CH2)nxe2x80x94COxe2x80x94(CH2)m-heterocyclyl, wherein alkyl, cycloalkyl, aryl and heterocyclyl are as defined above, and n and m, being the same or different, are zero or an integer of 1 to 5, and wherein the alkyl, cycloalkyl, aryl and heterocyclyl groups are optionally substituted by one to three substituents selected from chloro, fluoro, cyano, cyanomethyl, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkylsulfonyl, phenyl, tolyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-phenoxyphenyl, 4-(4-pyridyl)oxyphenyl, pyridyl, or R3 is selected from isobutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and cyclopentylmethyl; or R3 is selected from 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, wherein the phenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl, propyl, butyl, mesyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy; or R3 is selected from phenylsulfonylmethyl or phenylsulphonylethyl, wherein the phenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4-fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy;
Q is:
a group xe2x80x94CONHG, xe2x80x94CONGGxe2x80x2, xe2x80x94CONHxe2x80x94CHGGxe2x80x2, CON(CH3)xe2x80x94CHGGxe2x80x2, xe2x80x94CONHxe2x80x94CH2xe2x80x94CHGGxe2x80x2, or xe2x80x94CON(CH3)xe2x80x94CH2xe2x80x94CHGGxe2x80x2, wherein G and Gxe2x80x2, being as defined above, are preferably selected from C1-C6 straight or branched alkyl, C5-C6 cycloalkyl, phenyl, tolyl, methylenedioxyphenyl, piperonyl and pyridyl, either unsubstituted or substituted by one to three substituents selected from chloro, fluoro, hydroxy, hydroxymethyl, C1-C4 alkoxy, amino, methylamino, dimethylamino, C1-C4 alkyl, C3-C7 cycloalkyl, xe2x80x94CONH2, xe2x80x94CONHCH3, xe2x80x94CONHC(CH3)3, xe2x80x94CONH(4-fluorophenyl), xe2x80x94CONH-pyridyl, xe2x80x94CONH-(methylenedioxy)phenyl, xe2x80x94CONH-piperonyl, carbomethoxy, carbethoxy, or a keto group xe2x80x94COxe2x80x94RII, wherein RII, being as defined above, is selected from C1-C4 alkyl, phenyl, fluorophenyl, chlorophenyl, methylenedioxyphenyl, naphthyl, piperonyl, or a sulfone xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94RII, wherein n and RII are as defined above, or a sulfonamide xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94SO2NHRII, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRII RIII, wherein n, RII and RIII are as defined above, including the special case wherein RII and RIII, taken together with the nitrogen atom to which they are attached, constitute an azaheterocyclyl ring, as defined above; or
a group xe2x80x94CO-azaheterocyclyl, wherein azaheterocyclyl, being as defined above, is, either unsubstituted or substituted by one to three substituents selected from hydroxy, hydroxymethyl, C1-C4 alkoxy, carbamoyl, carbomethoxy, carbethoxy, mesyl, C1-C6 linear or branched alkyl, trifluoromethyl, C3-C7 cycloalkyl, aryl, heterocyclyl and aryl-(C1-C3)alkyl or heterocyclyl-(C1-C3)alkyl; or said azaheterocyclyl group is substituted by a group xe2x80x94CONHxe2x80x94RII, wherein RII, being as defined above, is selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-piperidyl, 2-thiazolyl, 1-naphthyl, 2-naphthyl, 3-quinolyl, 5-quinolyl, 3-isoquinolinyl, 5-isoquinolyl, 3-quinuclidinyl, methylenedioxyphenyl, piperonyl, 2-benzimidazolyl and 5-tetrazolyl; or said azaheterocyclyl group is substituted by a keto group xe2x80x94COxe2x80x94RII, or by a carbinol group of formula xe2x80x94CH(OH)xe2x80x94RII, wherein RII, being as defined above, is selected from C1-C4 alkyl, phenyl, fluorophenyl, chlorophenyl, methylenedioxyphenyl, naphthyl, piperonyl, or by a sulfone xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94RII, wherein n and RII are as defined above, or by a sulfonamide xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NHRII, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRII RIII, wherein n, RII and RIII are as defined above, including the special case wherein RII and RIII, taken together with the nitrogen atom to which they are attached, constitute an azaheterocyclyl ring, as defined above;
and the salts and solvates thereof.
When, in the above embodiment R1 and R2 form an azaheterocyclyl ring, the azaheterocyclyl ring is preferably selected from aziridine, azetidine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine, succinimido, phthalimido, saccharinyl, hydantoinyl, and oxoisoindolinyl. When R2 is xe2x80x94CO-azaheterocyclyl or xe2x80x94SO2-azaheterocyclyl, the azaheterocyclyl moiety is preferably morpholino or piperidino. When Q is a group xe2x80x94CO-azaheterocyclyl, the azaheterocyclyl moiety is preferably selected from azetidine, morpholine, thiomorpholine, pyrrolidine, piperidine. piperazine, pyridazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine and hexamethylenimine. The aryl group or moiety in the definitions of Q is preferably selected from phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, methylenedioxyphenyl, naphthyl, and heterocyclyl is preferably pyridyl.
A further preferred group of compounds are cyclic acetonide prodrugs of formula (IIxe2x80x2): 
wherein R2, R3 and Q are as defined above and T is methyl or a hydrogen atom, and Txe2x80x2 is methyl, C2-C4 lower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, methylamino, dimethylamino, chloro and fluoro. More preferably, T and Txe2x80x2 are methyl.
The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active ingredient, a compound of the invention as defined above.
Compounds of the general formula (I) may be prepared by any suitable method known in the art, and/or by the following processes, which form another aspect of the invention. In the description and formulae below, the groups W, R1, R2, R3 and Q are as defined above. It is understood that in the processes below any functional group (e.g. carboxyl, hydroxyl or amino), if needed or desired, can be masked by conventional methods and unmasked at the end or when convenient. Suitable protecting groups for such functionalities will be apparent to those skilled on the art and are well described in the chemical literature (see. for example: xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, Wiley Interscience). It is also understood that any of the groups W, R1, R2, R3 and Q can be converted by conventional methods into different groups W, R1, R2, R3 and Q having any of the meaning previously defined, if desired, at the end or at any stage of the processes below. These conversions are known or will be apparent to those skilled in the art and are well described in the chemical literature (see, for example: xe2x80x9cComprehensive Organic Transformationxe2x80x9d by R. C. Larock, VCH Publishers).
A preferred process for preparing a compound of formula (I) comprises:
(a) reacting a beta-lactam compound of formula (III): 
wherein R2 and R3 are as defined above, and Wxe2x80x2 is COOH, CONHOH or a protected derivative thereof, with:
xe2x80x83a primary or secondary acyclic amine of formula Gxe2x80x94NH2, GGxe2x80x2NH, GGxe2x80x2CHxe2x80x94NH2, GGxe2x80x2CHxe2x80x94NHCH3, GGxe2x80x2CHxe2x80x94CH2xe2x80x94NH2, or GGxe2x80x2CHxe2x80x94CH2xe2x80x94NHCH3, wherein G and Gxe2x80x2 are as defined above; or
a cyclic saturated or unsaturated secondary amine, represented as azaheterocyclyl-H, wherein azaheterocyclyl is as defined above; to obtain a compound of formula (IV): 
wherein Wxe2x80x2, R2, R3 and Q are as defined above; and then:
(b) converting said compound of formula (IV) into a compound of formula (I), wherein W, R1, R2, R3 and Q are as defined above; and then:
(c) if desired , removing the protecting groups and/or, if desired, converting any of the groups W, R1, R2 R3 and Q into different groups W, R1, R2, R3 and Q at the end or at any stage of the process.
It is evident that compounds with a desired configuration may be prepared starting from compounds (III) and (IV) with the appropriate configurations. Thus, a process for preparing preferred compounds of formula (Ixe2x80x2) comprises:
(axe2x80x2) reacting a beta-lactam compound of general formula (mxe2x80x2): 
wherein R2 and R3 are as defined above, and Wxe2x80x2 is either COOH, CONHOH, or a protected derivative thereof, with an amine as defined above, to obtain a compound of formula (IVxe2x80x2): 
wherein Wxe2x80x2, R2, R3 and Q are as defined above; and
(bxe2x80x2) converting this compound of formula (IVxe2x80x2) into a compound of formula (Ixe2x80x2): 
wherein W, R1, R2, R3 and Q are as defined above.
The reaction between the beta-lactam of formula (III) or (IIIxe2x80x2) and an amine among those hereabove detailed in step (a) or (axe2x80x2) above can be carried out in organic solvents, especially dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), acetonitrile, dimethylsulfoxide (hereinafter DMSO) and toluene, or in aqueous organic solvents, especially aqueous THF, aqueous DMF, and aqueous acetonitrile, at temperatures ranging from 0 to 120xc2x0 C., either in the absence or in the presence of external bases. When the amine is a poor nucleophile, in order to accelerate the reaction, and achieving higher yields of the product of formula (IV) or (IVxe2x80x2), the reaction can be run in the presence of nucleophiles (NuH or salts thereof, wherein Nu is herebelow defined), which cleave the beta-lactam of formula (III) or (IIIxe2x80x2) more readily. In this case, an intermediate of formula (IIIa) or (IIIxe2x80x2a) is formed: 
wherein Wxe2x80x2, R2 and R3 are as defined above, and Nu is selected from the group consisting of azido, imidazole, cyano, lower alkylthio, pyridylthio, phenylthio, and benzylthio. Said intermediate of formula (IIIa) or (IIIaxe2x80x2), being an activated carboxylic acid derivative, reacts in the same milieu or in a separate step, and under the same reaction conditions, with the amine selected among those detailed above, giving rise to the product of formula (IV) or (IVxe2x80x2). Particularly preferred external nucleophiles are sodium azide, imidazole, and sodium and potassium cyanide; particularly preferred solvents are DMF and acetonitrile.
When in compounds of formula (III), (IIIxe2x80x2), (IV), (IVxe2x80x2) above Wxe2x80x2 is a protected carboxy derivative, it is preferably benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, trimethylsilyloxycarbonyl, tert-butyldimethyl-silyloxycarbonyl, phenyl-dimethyl-silyloxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n-butoxycarbonyl. When in compounds of formula (III), (IIIxe2x80x2), (IV), (IVxe2x80x2) above Wxe2x80x2 is a protected derivative of CONHOH, it is preferably a group of formula CONHOR10 or CON(R11)OR10, wherein R10 and R11 are, respectively, hydroxy- and amino-protecting groups, known per se and removable by hydrogenolysis or by hydrolysis. Preferred R10 and R11 groups, which may be the same or different, include benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, tert-butyl, tert-butoxycarbonyl, tetrahydropyranyl, and trityl.
The conversion of a compound of formula (IV) or (IVxe2x80x2) into a compound of formula (I) or (Ixe2x80x2) in step (b) above may include any or all of the following steps in any order:
(bi): the conversion of the group Wxe2x80x2, which is a protected carboxy or hydroxamate derivative, into a group W, which is the unmasked carboxy or hydroxamic acid. This conversion is carried out by methodologies for unmasking of protective groups, which are well known in the art, as generally referred to above. A preferred conversion of this type is hydrogenolysis, especially in the presence of a palladium catalyst, in an inert organic solvent such as ethanol or DMF or the like, especially at room temperature and under atmospheric pressure or moderate pressure, which is suitable for the conversion, e.g., of benzyl and p-nitrobenzyl esters into the parent carboxylic acids, or of O-benzyl and O,N-bis-benzyl hydroxamates into the parent hydroxamic acids. Another preferred conversion of this type is acid hydrolysis, especially by trifluoroacetic acid, hydrochloric acid, or by aluminium trichloride, in the presence or absence of anisole, in inert organic solvents such as THF, acetonitrile and the like, especially between xe2x88x9220 and +30xc2x0 C., which is suitable for the conversion, e.g., of tert-butyl esters and p-methoxybenzyl esters into the parent carboxylic acids, or of O-tert-butylhydroxamates, O-(p-methoxybenzyl)-hydroxamates, and O,N-bis(p-methoxybenzyl)hydroxamates into the parent hydroxamic acids. A further preferred conversion of this type is alkalyne hydrolysis, especially by NaOH, KOH, LiOH, KOSi(CH3)3, in an inert organic solvent or in water or in admixtures thereof, which is particularly suitable for the conversion of lower alkyl esters, e.g. the methyl, ethyl and n-butyl esters, into the parent carboxylic acids.
(bii): the conversion of the group Wxe2x80x2, which is carboxy or an activated derivative thereof, into a group W, which is xe2x80x94CONHOH. This conversion entails the condensation of such compounds of formula. (IV) with hydroxylamine or a salt thereof, or with an O-protected hydroxylamine of formula R10Oxe2x80x94NH2, or an N,O-diprotected hydroxylamine of formula R10Oxe2x80x94NHR11, wherein R10 and R11 are as defined above, or a salt thereof, and then removal of said protecting groups R10 and R11, if present, according to (bi) above. Such condensation is carried out according to general methodologies for the conversion of carboxylic acids or activated derivatives thereof into hydroxamic acids, which are well known in the art. In particular, activated derivatives of the carboxy group are the acid chloride, mixed anhydrides, and esters. In particular, the acid chloride is obtained by reacting the acid or a salt thereof with reagents such as oxalyl chloride or thionyl chloride; mixed anhydrides are obtained by reacting the acid or a salt thereof with chlorocarbonates, such as ethyl chlorocarbonate, or with acid halides, such as pivaloyl chloride; esters, which are, preferably, the methyl, ethyl, n-butyl, pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl esters, are obtained by reaction of the acid with the corresponding alcohols in the presence of a dehydrating agent, for example dicyclohexyl carbodiimide (hereinafter DCC), N,N-dimethylaminopropyl-Nxe2x80x2-ethyl carbodiimide (EDC), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). Esters, in particular the methyl, ethyl, and n-butyl esters, may be present from the beginning in the azetidinone intermediates of formula (III) and (IIIxe2x80x2) above. An O-protected hydroxylamine is, preferably, O-benzylhydroxylamine, O-tert-butylhydroxylamine, O-tert-butyldiphenylsilyl hydroxyamine, O-(4-methoxybenzyl)-hydroxylamine, O-(4-nitrobenzyl)hydroxylamine, O-trimethylsilylhydroxylamine, and O-(tert-butoxycarbonyl)hydroxylamine. An N,O-diprotected hydroxylamine is, preferably, N,O-bis(benzyl)hydroxylamine, N,O-bis(4-methoxybenzyl)hydroxylamine, N,O-bis(tert-butoxycarbonyl)hydroxylamine, N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)hydroxylamine, and N-(tert-butoxycarbonyl)-O-(tetrahydropyranyl)hydroxylamine. Preferably, the condensation reaction with hydroxylamine, O-protected hydroxylamines, N,O-diprotected hydroxylamines, and the salts thereof, is carried out in an inert organic solvent, such as DME, THF, acetonitrile, dichloromethane, toluene and the like, at temperatures ranging from xe2x88x9220 to +60xc2x0 C., optionally in the presence of a tertiary organic base, such as triethylamine and N-methylmorpholine. When protected hydroxylamines are employed, the protecting groups are removed after the condensation reaction, under the conditions described in (bi) above;
(biii): the conversion of the group NHR2, being R2 different from hydrogen, into a group NH2. This reaction can be carried out on compounds of formula (I), (Ixe2x80x2), or on intermediates of formula (IV), (IVxe2x80x2), wherein R2 is an amino protecting group, according to methods well known per se, for example by the methods of removal of amino protecting groups which are part of the techniques of peptide chemistry. Particularly preferred R2 groups for such conversion are electron-withdrawing groups, in particular alkoxy- or benzyloxy-carbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl and 4-nitro or 4-methoxy derivatives thereof, since the same particular R1 groups efficiently assist the beta-lactam cleavage reaction detailed in step (a) above. In a preferred embodiment of the present invention, R2 is tert-butoxycarbonyl, which can be removed by treatment with trifluoroacetic acid (TFA), optionally in the presence of anisole, in an inert organic solvent; in another preferred embodiment, R2 is benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, which can be removed by catalytic hydrogenation;
(biv): the conversion of the group NHR2, including the special case wherein R2 is hydrogen, into a group NR1R2, to be selected within the specifications stated above. Preferred R1 and R2 groups are the same groups detailed for the preferred compounds of formula (I). Such conversion encompasses functionalizations of amino groups well known in the art, such as alkylation, acylation, sulfonylation, and the like, and is performed according to methods well known per se. In a preferred embodiment of the present invention, such conversion is performed on compounds of formula (IV) or (IVxe2x80x2) wherein Wxe2x80x2 is protected carboxy, thereafter removing the protecting group to obtain a compound of formula (I) or (Ixe2x80x2) wherein W is carboxy, by the general methodology described under (bi) above and, optionally, by converting the so-obtained compound of formula (I) or (Ixe2x80x2) wherein W is carboxy into the corresponding compound wherein W is xe2x80x94CONHOH, by the general methodology described under (bii) above,
(bv): the conversion of any group W, R1, R2, R3 and Q into any different group R1, R2, R3 and Q, to be selected within the specifications stated above, by methodologies known per se. The resultant compounds of formula (I) or (Ixe2x80x2) may be converted into the desired salts, prodrugs, hydrates or solvates thereof by means of well known reactions, which include salt preparation by reaction with a pharmaceutically acceptable acid, or conversion of any hydroxy or carboxy group into an ester thereof if desired, by condensation with a pharmaceutically acceptable alcohol or with a pharmaceutically acceptable carboxylic acid. In the particular case of the cyclic prodrugs described by formula (II) or (IIxe2x80x2), said compounds are obtained from the corresponding compounds of formula (I) or (Ixe2x80x2) wherein W is xe2x80x94NHOH and R1 is hydrogen, by reaction with an aldehyde of general formula Txe2x80x94CHO or a ketone of general formula TTxe2x80x2CO, wherein T and Txe2x80x2 are as defined above, and removing water by evaporation.
The amines used in step (a) above are known compounds or are prepared from known compounds by known methods.
The beta-lactams of formula (III) or (IIIxe2x80x2) above are known compounds or can be prepared from known compounds by methodologies known per se or by analogy with the specific preparative examples herein. In particular, a preferred preparation of compounds of formula (III) or (IIIxe2x80x2) includes:
(di): cyclization of an aspartic acid derivative to obtain a compound of formula (III) or (IIIxe2x80x2) wherein R3 is hydrogen, by reaction with a suitable condensing agent;
(dii): conversion of a compound of formula (III) or (IIIxe2x80x2) wherein R3 is hydrogen into a compound of formula (III) or (IIIxe2x80x2) wherein R3 is as described above, by deprotonation with a strong base and alkylation of the resulting beta-lactam enolate with an agent of formula R3xe2x80x94X, wherein X is halo, e.g. chloro, bromo or iodo, or sulfonyloxy, e.g. triflate, mesylate or the like.
General conditions for step (di) above are described in the literature, the preferred aspartic acid derivative being usually dibenzyl aspartate or di(4-nitro)benzyl aspartate. Some of the resultant azetidinones (III) or (IIIxe2x80x2) wherein R3 is hydrogen, Wxe2x80x2 is carboxy or an ester thereof, and R2 is hydrogen or tert-butyldimethylsyl are also commercially available. A preferred compound in step (dii) is a compound of formula (III) or (IIIxe2x80x2) wherein R3 is hydrogen, R2 is tert-butyldimethylsilyl, and Wxe2x80x2 is free carboxy, since the carboxylate anion helps at avoiding racemization at the azetidinone 4-C, and increases regioselectivity of alkylation by the R3xe2x80x94X reagent at the azetidinone 3-C.
The conditions described in steps (a), (b), (c) and (d) do not usually promote epimerization or racemization at pre-existing chiral centers. Thus, when the aspartic acid derivative used as a reagent in step (di) above is an L-aspartic acid derivative, the reaction affords a chiral azetidinone of formula (IIIxe2x80x2), wherein R3 is hydrogen and R2, Wxe2x80x2 are as described above. In such chiral azetidinone of formula (IIIxe2x80x2) wherein R3 is hydrogen, the configuration at the C-4 atom addresses stereoselective alkylation, by the R3xe2x80x94X reagent, in a transoid relationship with the Wxe2x80x2 substituent. Therefore, starting from such intermediates of formula (IIIxe2x80x2), step (dii) above stereoselectively affords the corresponding azetidinones of formula (IIIxe2x80x2) wherein R3, being as described above, is different from hydrogen, with the depicted configurations at the two chiral centers. Said configurations of the two chiral centers are the same as found in compounds of formula (Ixe2x80x2) herein specifically preferred. Accordingly, it can be appreciated that steps (di) and (dii) above are essential part of an original, fully stereocontrolled route to the compounds of formula (Ixe2x80x2).
Another process for the preparation of compounds of formula (I) comprises:
(e) alkylation of an aspartic acid derivative of formula (V): 
wherein Wxe2x80x2 is either carboxy or a protected derivative thereof, Qxe2x80x2 is either Q as described above, or carboxy or protected carboxy, and R1, R2 are as described above, with a reagent of formula R3xe2x80x94X, wherein R3 and X are as described above, to obtain a compound of formula (VI): 
wherein Wxe2x80x2, R1, R2, R3 and Qxe2x80x2 are as described above; and:
(f) conversion of such compound of formula (VI) into the desired compound of formula (I), wherein W, R1, R2, R3 and Q are as described above.
We have observed that the configuration at the chiral carbon atom in compounds of formula (V) addresses the configuration at the new chiral center in the product of formula (VI) in an anti-fashion, exclusively or predominantly. Thus, starting from an L-aspartic derivative of formula (Vxe2x80x2): 
wherein Wxe2x80x2, R1, R2, R3 and Qxe2x80x2 are as described above, step (e) predominantly or exclusively affords a compound of formula (VIxe2x80x2): 
wherein Wxe2x80x2, R1, R2, R3 and Qxe2x80x2 are as described above, from which the preferred compounds of formula (Ixe2x80x2) are obtained by step (f) above.
The reaction of step (e) above is carried out according to conventional carbanion chemistry, i.e. with 2-4 equivalents of a strong base, such as LDA and the like, in aprotic organic solvents, such as THF, DMF, N-methylpyrrolidone, HMPA and the like, at temperatures ranging from xe2x88x9270xc2x0 C. to room temperature. A preferred Wxe2x80x2 group is free carboxy. A preferred R1 group is hydrogen. A preferred R2 group is tert-butoxycarbonyl. Preferred Qxe2x80x2 groups are either the acyclic or cyclic tertiary carboxamides described within Q above, or a carboxy ester, which in step (f) can be converted into the group Q above as generally known for the preparation of carboxamides.
The compounds of formula (I) and (Ixe2x80x2) provided by the present invention are characterized by high inhibitory activity on matrix metalloproteinases (MMPs), especially collagenases, gelatinases and stromelysins. For example, the following protocol was used to assess the biochemical activity of compounds of formula (Ixe2x80x2) against MMP-1, MMP-2, and MMP-3 (respectively, human interstitial collagenase, gelatinase A, and stromelysin-1).
Biochemical Assay (Protocol A)
Human collagenase (MMP-1) was obtained as truncated recombinant enzyme encompassing residues 101-269 and did not require activation. Human gelatinase-A (MMP-2) was obtained as pro-enzyme (72 kDa) and was activated with 1 mM 4-aminophenylmercuric acetate for 30 min at 37xc2x0 C. immediately prior to use. Human stromelysin-1-255 (MMP-3) was obtained as a recombinant pro-enzyme isolated from E. coli and activated by heat (1 h, 55xc2x0 C.).
The substrate was the commercial quenched-fluorescence peptide Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, that is (7-methoxycoumarin4-yl)Acetyl-Pro-Leu-Glv-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diamino-propionyl)-Ala-Arg-NH2 (C. G. Knight et al., FEBS Lett.296:263, 1992). The enzymes cleave at the Gly-Leu bond, removing the internally quenching Dpa group. Release of the highly fluorescent peptide Mca-Pro-Leu was followed fluorimetrically at 37xc2x0 C. using a Perkin Elmer LS-50 Fluorescence Spectrophotometer fitted with a thermostatted four position stirring cell changer. The excitation wavelength was set at 326 nm (bandwidth 5 nm) and the emission at 392 nm (bandwidth 20 nm). Km values of this substrate for the three MMP""s is 70 xcexcM or more (Knight et al., reference above). Substrate concentration was 2 xcexcM in the tests, so that we could approximate to unit the term (1+[substrate]/KM) in calculations. The substrate was stable for over 60 minutes in the assay conditions, giving no appreciable increment of fluorescence. Full response was adjusted against 200 nM Mca-Pro-Leu-OH (the released fluorescent peptide) and the instrument was calibrated in the range 0-100 nM Mca-Pro-Leu-OH, corresponding to 0-5% extent of hydrolysis of the 2 xcexcM substrate. The aqueous assay buffer was 50 mM Tris/HCl pH=7.4 containing 0.15 M NaCl, 10 mM CaCl2, 0.01 mM ZnCl2 and 0.05% Brij 35. The concentration of the activated enzyme was determined by titration against representative inhibitors described in the literature and synthesized in house: Roche Ro31-9790 (N. G. Knebel et al., J. Chromatogr. B 673:213, 1995) for MMP-1, and Celltech CT-1418 (compound 1 in S. K. Chander, J. Pharm. Sci. 84:404, 1995) for MMP-2 and MMP-3. Enzyme concentrations in the tests were set at 1.0 nM for MMP-1, 0.04 nM for MMP-2, and 3.0 nM for M-3. Under our assay conditions, we measured keat/KM values of 26900, 669000 and 9740 1/(Mxc3x97s) for MMP-1, MMP-2 and MMP-3, respectively. All the three enzymes were found stable for over three hours in the assay conditions.
The inhibition constant for compounds of the present invention was measured at steady state (Ki*; see J. F. Morrison and C. T. Walsh, Adv. Enzymol. Relat. Areas Mol. Biol. 61:201, 1988), upon preincubation experiment, by measuring V0, the initial rate in the absence of inhibitor, and Vs, the steady-state velocity, at different concentrations of inhibitors in the region of their enzyme-inhibitor dissociation constants.
On a routine basis, 1.94 mL of assay buffer was pre-heated at 37xc2x0 C. in a vial, 0.02 mL of inhibitor in DMSO (or DMSO only), and 0.02 ml of 100 nM MMP-1 or 4 nM MMP-2 or 300 nM MMP-3 were added, mixed, and the vial was held at 37xc2x0 C. for 5-180 minutes. Then 0.02 ml of 0.2 mM substrate was added, mixed and transferred into a pre-heated cell. The sample was allowed to equilibrate in the cuvette for 3-5 min at 37xc2x0 C. against small changes in temperature and changes in the enzyme-inhibitor equilibria related to addition of substrate. After that, the linear increase of fluorescence was monitored over 3-5 min, and the slope (Vo or Vs) was obtained. Inhibitor concentrations were varied to collect data over Vs/Vo ratio ranging from 0.05 to 0.95. The values of Ki* were calculated by nonlinear weighted regression to the tight-binding equation according to Morrison and Walsh above:
Vs/Vo=[1/(2xc3x97Et)]xc3x97SQR[(Ki*+Itxe2x88x92Et){circumflex over ( )}2+4xc3x97Ki*xc3x97Et]xe2x88x92(Ki*+Itxe2x88x92Et)
wherein Et is the total enzyme concentration, and It is the total inhibitor concentration. The following Table I lists Ki* obtained for some representative examples:
Some of the compounds of formula (I) were also shown to possess high activity at inhibiting the release of TNF of several different cell lines, under different stimulation conditions. For example, the following cell-based assay was used to assess such activity:
Cellular Assay (Protocol B)
THP-1 cells, cultured in RPMI 1640 supplemented with 10% FCS, were distributed into 24-well plates, 1 mL of a suspension of 1xc3x97106 cells/mL in each well. Compounds to be tested, dissolved in DMSO and diluted with the culture medium (1% final DMSO concentration) were added. Plates were incubated for 30 min at 37xc2x0 C. in 5% CO2, and lipopolisaccharide (LPS 0111:B4, 5 xcexcg/ml) was added as a stimulant. After a further 4 h incubation, cells were harvested, centrifuged (2,000 rpm, 7 min), and the surnatant was collected and freezed (xe2x88x9220xc2x0 C.) until analysis. Analysis was run by classical ELISA methodology (monoclonal anti-TNF-a antibody, rabbit capture policlonal antibody, and peroxidated anti-rabbit antibody). Dichloroisocoumarin was used as a standard. As anticipated above, low aqueous solubility, metabolic instability (high clearance) and poor oral bioavailability is a common problem for the xe2x80x9cpeptide-basedxe2x80x9d hydroxamates of the prior art. In these respects, the compounds of the present invention are usually characterised by a superior profile. As an example, Table 2 reports the solubility in water for some representative compounds, detailed in the Examples.
As a further example, Table 3 reports clearance and AUC values measured after intravenous administration to rats of a 10-15 mg bolus dose of some representative compounds of the present invention.
As an additional example, Table 4 reports the maximum plasma concentration (Cmax) and oral bioavailability (% F; calculated from dose-normalised ratio of oral to i.v. mean AUC values) after oral administration to rats or cynomolgus monkeys of a 10-15 mg single dose of some representative compounds of the present invention.
Compounds of formula (I) can be used in human or veterinary medicine in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. Thus, a distinct aspect of the present invention is the preparation of pharmaceutical compositions carrying a compound of formula (I) as active ingredient, and a method of management (i.e. treatment or prophylaxis) of diseases or conditions mediated in humans and warm blood animals by MMPs and/or TACE, which method comprises administering an effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.
In particular, the compounds of formula (I) can be administered:
A) Orally, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents;
B) Parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables,
C) By inhalation, in the form of aerosols or solutions for nebulizers,
D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and poly-ethylene glycols;
E) Topically, in the form of creams ointments, jellies, solutions or suspensions.
Daily doses are in the range of about 0.1 to about 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease, and the frequency and route of administration; preferably, daily dosage levels for humans are in the range of 10 mg to 2 g. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans, may contain from 5 mg to 2 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 1 g of active ingredient.
Pharmaceutical compositions containing a compound of formula (I) can be used in medicine for the treatment of disease states characterised by a systemic or local imbalance of active MMPs and their natural inhibitors. The rationale for the use of MMP inhibitors in medicine has been illustrated above, and is well described in the recent literature, see, for example, D. E. Levy and A. M. Ezrin, xe2x80x9cMatrix Metalloproteinase Inhibitor Drugsxe2x80x9d, in: Emerging Drugs: The Prospect for Improved Medicines, Chapter Ten (pp 205-230), Ashley Publications Ltd., 1997. According to this rationale, and proofs of concept already established with other MMP inhibitors, the compounds of the present invention can be used, in particular, for the treatment of:
inflammatory and autoimmune diseases, especially rheumatoid arthritis, osteoarthritis, bone resorption, periodontal disease, multiple sclerosis, inflammatory bowel diseases;
cancer, including both tumor growth and tumor invasion by secondary metastases, with particular reference to breast cancer, small cell lung cancer, non-small cell lung cancer, glioblastoma, prostate cancer, ovarian cancer, gastric and esophageal cancers, pancreatic cancer, colorectal tumors, and bony metastases;
angiogenic disorders, especially diabetic retinopathies and macular diseases,
cardiovascular diseases, especially congestive hearth failure and vascular restenosis;
soft and osseous tissue diseases, including ocular inflammation, corneal or tissue ulceration, wound healing;
other disorders in which either MMs or abnormal release of TNF-alfa is implicated, in particular shock syndromes, transplant rejection, cachexia, anorexia. The present invention also includes the use of compounds of formula (I), for the treatment of any of the diseases above, as adjuncts to other conventional treatments; for example, together with anti-inflammatory or immunosuppressive drugs for the treatment of rheumatoid arthritis and multiple sclerosis, and together with cytotoxic or cytostatic drugs for the treatment of tumoral diseases.